Discovery of EBI-907: A highly potent and orally active B-Raf^V600E inhibitor for the treatment of melanoma and associated cancers

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• 作者：Biao Lu^a ; ; Hu Cao^a ; Jingsong Cao^b ; Song Huang^a ; Qiyue Hu^a ; Dong Liu^b ; Ru Shen^b ; Xiaodong Shen^a ; Weikang Tao^a ; Hong Wan^a ; Dan Wang^a ; Yinfa Yan^b ; Liuqing Yang^b ; Jiayin Zhang^b ; Lei Zhang^a ; Lianshan Zhang^c ; Minsheng Zhang^b
• 关键词：B-RafV600E ; Kinase ; Pyrazolo[3 ; 4-c]isoquinoline ; Scaffold hopping ; Cancer
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 February 2016
• 年：2016
• 卷：26
• 期：3
• 页码：819-823
• 全文大小：1695 K

文摘

A novel series of pyrazolo[3,4-c]isoquinoline derivatives was discovered as B-Raf^V600E inhibitors through scaffold hopping based on a literature lead PLX4720. Further SAR exploration and optimization led to the discovery of potent B-Raf^V600E inhibitors with good oral bioavailability in rats and dogs. One of the compounds EBI-907 (13g) demonstrated excellent in vivo efficacy in B-Raf^V600E dependent Colo-205 tumor xenograft models in mouse and is under preclinical studies for the treatment of melanoma and B-Raf^V600E associated cancers.